In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early post-transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donorderived T cells, including GvH clones, and CD34 + HSPCs were simultaneously detected in the recipients' bone marrow (BM) >100 days post-transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined cytotoxic single cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.

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Background: Colorectal cancer (CRC) is the third leading cause of cancer-related death in both sexes in the United States. While the overall CRC incidence rates have declined over the past 10 years, the disparity between African Americans (AAs) and non-Hispanic whites has increased and the incidence in AAs remains higher than in other populations. Very few studies have specifically addressed CRC in AAs, and important studies on CRC almost never include significant numbers of AAs to draw any firm conclusions. Objective: To establish a large, robust and well-characterized database and bio-repository collection of CRC from AA patients and controls strengthening a collaborative working group, the Chicago Colorectal Cancer Consortium (CCCC), which spans 5 of the main hospitals of the Chicago area. We collect clinical, demographic and dietary data; and a biological repository of specimens consisting of tumor and non-tumor genomic DNA, RNA, plasma, serum, and paraffin-embedded samples. Specific Aims: The primary goal of the project is to study how genetic and environmental factors and their interaction result in the development of CRC. We will also study prognosis determinants in the AA population. Results: Recruitment and data collection: So far we have recruited 56 AA and 17 white-non Hispanic adenocarcinoma colorectal patients. We have also recruited 84 AAs and 32 white patients with adenomatous polyps, and 44 AAs and 30 white controls (individuals without polyps or previous history of polyps). From all individuals we have collected demographic/socioeconomic data, clinical data, family history of cancer, medication and toxic substance history, and dietary data using the Block Brief 2000 Food Frequency Questionnaire. Preliminary analyses: To identify potential variables that could influence the cancer disparity between AAs and whites, we performed a preliminary analysis of all these data using a Fisher exact test. A systematic molecular analysis of BRAF and KRAS mutations, microsatellite instability and presence of CpG island methylation phenotype in all CRC tumors is being performed. We are also analyzing protein expression of the mismatch repair genes through immunohistochemistry. We will test for an association between these molecular features and clinical variables. Moreover, 1 year follow-up data is already available and being collected on 23 cases. Therefore, we will soon be able to start investigating the relationship of those molecular features with survival and specific chemotherapy response. Summary: The preliminary analysis has highlighted some significant differences between AA and white CRC patients. In comparison with white patients, a higher proportion of AA patients are less than 50 years at diagnosis, take NSAIDS, and fulfill Bethesda criteria, which is a set of criteria to select out patients to be pre-screened for mismatch repair deficiency and eventually for genetic testing to rule out Lynch syndrome. It has also highlighted that CRC patients have a lower level of education than cancer-free individuals in both ethnicities. This type of sociocultural disparities could potentially be associated with different life styles. In fact, AA CRC cases consumed more carbohydrates than controls reflecting this potential life style difference. Cancer Relevance: Understanding the key molecular features and environmental factors that impact CRC development in the AA population is of paramount importance given the scarce information available. Understanding the role genetic factors will be crucial to help risk stratify patients, recommend screening modalities, and recommend preventive measures. When this information is combined with environmental factors, such as dietary habits, we will be able to offer a comprehensive personalized medicine approach for AA CRC patients. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B73.

Colorectal cancer (CRC) affects disproportionally African Americans (AAs) who have a 20% higher incidence and a 40% higher mortality than Caucasians. Very few studies have specifically addressed CRC in AAs. In order to uncover the factors that underlie this disparity we set up the CCCC, a large, robust and well-characterized database and biorepository of CRC patients from the Chicago metropolitan area that is highly enriched with AAs. The project enrolls newly diagnosed CRCs, polyps at different stages, and cancer/polyp-free controls in 5 large hospitals. Extensive clinical, family history, demographic, dietary, toxic exposure data is collected along with tumor and uninvolved mucosa as well as plasma, serum, and paraffin-embedded samples. Tumors are molecularly characterized and germline DNA is used to assess genetic factors implicated in CRC development. The primary goal of the project is to study how genetic and environmental factors as well as their interaction contribute to CRC development and which factors make AAs more prone to develop this cancer. We will also assess specific factors that may contribute to the worse prognosis in AAs. Results: A total of 205 CRCs, (58% AAs), 86 patients with high-risk adenomas, 75 mild-risk adenomas, and 173 controls have been recruited so far. The mean age at diagnosis was 60.2 for AAs and 61.8 for whites (P=0.08), in both cases significantly lower than the mean age reported for the US CRCs in general (68-70). There was a significantly higher number of AA patients younger than age 50 at diagnosis (19.5% vs. 7.1% whites; P=0.043). In AA patients tumors were more often on the right side of the colon (43.3% vs. 22.7%; P=0.02) and more were undifferentiated (19.1% vs. 3.5%; P=0.03). Both groups had a similar number of colonoscopies before cancer diagnosis (60.2% for AAs vs. 68.3% for whites; P=0.11). While there was no significant difference among AA cases and controls regarding high tobacco use (>20 pack/years)(16.9% cases vs. 17.1% controls), more whites with CRC were heavy smokers (45.7% cases vs. 29.7 controls). Less AA patients reported family history of CRC than whites (16.4% vs. 35.2%; P0.02) or family history of polyps (21.7% vs. 44%). Conclusions: In our urban cohort both AA and white patients present CRC significantly earlier than expected. Very important differences are seen between AAs and whites that may have significant implications when considering CRC screening approaches, such as the high percentage of AA patients diagnosed before age 50 or the much higher number of right-sided tumors. Heavy tobacco use seems to associate with CRC in whites but not in AAs. Altogether points towards important biological differences that need to be further assessed. As we are ascertaining toxic and dietary exposure and molecularly characterizing all tumors, eventually we should be able to explain the biological basis of the significant disparity in CRC Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3597. doi:1538-7445.AM2012-3597